[Paper-level Aggregated] PMCID: PMC5873857

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The BRAFV600E variant is described as leading to disordered vessel formation and recapitulating clinical features of vascular malformations (VMs), indicating its role in tumorigenesis. Functional: The structural modeling of variants, including deletions and missense mutations, suggests that they affect the integrity of the protein structure and function of MAP2K1, indicating a functional impact on the protein's activity. Predictive: The study demonstrates that treatment with vemurafenib, a BRAF inhibitor, improved blood flow in zebrafish models expressing BRAFV600E, suggesting predictive value for therapeutic response based on the presence of this variant.

Gene→Variant (gene-first): BRAF(673):BRAFV600E MAP2K1(5604):E62del NA:K57 MAP2K1(5604):c.159_173del MAP2K1(5604):c.173_187del MAP2K1(5604):p.[K57N]

Genes: BRAF(673) MAP2K1(5604) NA

Variants: BRAFV600E E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage describes how the BRAFV600E variant contributes to disordered vessel formation and recapitulates clinical features of vascular malformations, indicating its role in tumor development or progression. Predictive: The passage discusses the response of zebrafish with BRAFV600E to vemurafenib, an approved BRAF inhibitor, showing that the variant correlates with improved blood flow following targeted therapy.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants affect the 3D protein structure and stability of helix A in the MAP2K1 gene, indicating that they alter molecular function. Oncogenic: The variants are described as contributing to the destabilization of the conformation of the inactive state of the protein, which suggests a role in tumor development or progression.

Gene→Variant (gene-first): 5604:E62del NA:K57 5604:c.159_173del 5604:c.173_187del 5604:p.[K57N]

Genes: 5604 NA

Variants: E62del K57 c.159_173del c.173_187del p.[K57N]

[Paragraph-level] PMCID: PMC5873857 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of pathogenic variants in patients with vascular malformations (VMs), indicating that these variants are used to classify or define the clinical phenotype associated with the disease. Oncogenic: The identified variant c.159_173del is described as contributing to the allelic spectrum of variants in the RAS/MAPK pathway, which is known to be involved in tumor development and progression, thus supporting its oncogenic potential.

Gene→Variant (gene-first): 5604:c.159_173del

Genes: 5604

Variants: c.159_173del